Parkinsonism is characterized by a number of alterations in motor function, many of which fall into the category of positive signs (increased tone, involuntary movements) in Jacksonian terminology. A prominent neurochemical concimitant of this disease state is the marked reduction of dopamine levels in the neostriatum as a result of destruction in various degrees of the neurons supplying the dopaminergic innervation, namely those of the substantia nigra pars compacta. Although the positive signs of dysfunction may be caused by a subsystem failure, their pathophysiology cannot be attributed to the fact that a subsystem is no longer operative. Instead, it must be due to reorganization of the remaining components of the system particularly at the synaptic level. The specific aims of this proposal are to define the characteristics of this reorganization by studying the ultrastructure of various components of the besal ganglia system in an experimental monkey model of parkinsonism produced by the toxin 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP). Changes in the neuronal circuits will be assessed by comparison with normal material of the same species using mostly immunocytochemical methods to identify the elements containing one or more substances which may act as neurotransmitters and/or modulators. These techniques will also be applied at the light microscopic level in combination with Golgi impregnations to correlate the previously recognized neuronal types with their neurochemical content. Extensive use of computer assisted quantitative stereologic methods, whenever the nature of the experiment will permit their application, will aid in the discovery of more subtle alterations in the synaptic organization of the parkinsonian brain. The specific structures to be studied will be the neostriatum, pallidum, subthalamic nucleus and substantia nigra. If time allows, other nuclei to be investigated include the pedunculopontine, the locus ceruleus and the dorsal motor nucleus of the vagus nerve.